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Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation

The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstrea...

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Detalles Bibliográficos
Autores principales: Posseme, Celine, Llibre, Alba, Charbit, Bruno, Bondet, Vincent, Rouilly, Vincent, Saint-André, Violaine, Boussier, Jeremy, Bergstedt, Jacob, Smith, Nikaïa, Townsend, Liam, Sugrue, Jamie A., Ní Cheallaigh, Clíona, Conlon, Niall, Rotival, Maxime, Kobor, Michael S., Mottez, Estelle, Pol, Stanislas, Patin, Etienne, Albert, Matthew L., Quintana-Murci, Lluis, Duffy, Darragh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Author(s). 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237956/
https://www.ncbi.nlm.nih.gov/pubmed/35767946
http://dx.doi.org/10.1016/j.celrep.2022.110989
Descripción
Sumario:The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.